With $650 Million Gift, Psychiatric Disorders Once Again in Limelight at the Broad

By Bio-IT World Staff

July 23, 2014 | Ted Stanley, the philanthropist whose 2007 gift of $100 million formed the basis of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, has pledged an additional $650 million to the center to be distributed in multimillion dollar installments every year. The new gift will renew efforts at one of the largest organizations still pursuing research into the genetic basis of complex psychiatric conditions like schizophrenia, autism spectrum disorders, and bipolar disorder. While the rapid growth of massive genetic sequencing projects has led to great strides in understanding cancer and an assortment of rare hereditary diseases, the psychiatric disorders remain a discouraging field of study that has struggled to obtain interest and funding.

The Broad Institute chose to announce the grant this week, when work at the Stanley Center would be bolstered by a study of schizophrenia published on Tuesday in Nature. The new study, which was conducted by a massive international team in which the Broad Institute played a central role, is the largest genome-wide association study of any psychiatric disorder ever undertaken, as measured by the number of subjects. Altogether, over 38,000 individuals affected by schizophrenia were included in the study, in addition to nearly 115,000 controls. While many of the subjects had been separately analyzed in previous studies, over 20,000 schizophrenia cases were newly genotyped for this project. Subjects were genotyped using a variety of large SNP arrays, of which the Affymetrix Genome-Wide Human SNP Array 6.0 is representative, offering information on over 500,000 SNP loci and roughly 9.5 million total variants.

The Broad Institute has touted this study as representative of an inflection point in psychiatric research, brought on by ever-larger gene sequencing projects. "Scientists here at the Broad, and their collaborators around the world, are showing us that it's possible to begin to decode the biological basis of psychiatric disorders," said Eric Lander, President and Director of the Institute, in his address announcing the new gift and publication. The paper in Nature identifies over 100 loci in the genome that are associated with very high probability with a higher risk for developing schizophrenia, including 83 that had not been discovered through any previous study — information that could eventually lead to a better picture of the functional pathways that lead to the condition's symptoms.

However, like a pair of similar high-profile schizophrenia studies published earlier this year in Nature, the new work also underscores the sharp limits of a genetic approach to complex psychiatric disorders. The earlier papers, which Bio-IT Worldcovered in detail, looked at a smaller cohort of subjects, but used more comprehensive whole exome sequencing to search for relevant genetic variants. These studies too found numerous novel and previously-known regions of the genome associated with schizophrenia, including both rare and common variants, but failed to single out any single genetic pathway in more than a handful of cases.

While these large genome-wide association studies reliably pick up genes involved in certain biological functions — including calcium ion channels and neuroplasticity — as related to schizophrenia's pathology, the variety of genes implicated is growing, not shrinking, underscoring the fact that schizophrenia can be manifested through many routes and might even be considered a whole spectrum of diseases. This week's publication even ropes in genes related to the immune system. Further muddying the picture is a regularly observed overlap between genetic risk factors for schizophrenia and those for very different psychiatric conditions like autism. Although this research generates important new leads, it does not offer any easy path to true understanding of the cellular and system-wide causes of complex neurological conditions.

Given the Broad's position as a major center of genetic sequencing, and the clear understanding that the search for genetic markers for conditions like schizophrenia is far from exhausted, much of the new funding for the Stanley Center is likely to go toward more and larger genome-wide associations studies. Some of the funding, however, will be directed to more functional research, including cell line and mouse studies to parse the effects of variants that have already been found. With luck, Ted Stanley's new gift will push the Broad Institute one step closer to grasping the living biological processes behind psychological disorders. So far, the swift advance of genetics has done little more than illuminate how great that challenge is.